Superficial erosive gastritis may account for as much as 40% of upper gastrointestinal bleeding episodes. In most instances, bleeding from thee acute gastric erosions is related to the excessive use of salicylate- containing compounds or alcohol. Exposure of the gastric mucosa to luminal aspirin or alcohol results in a significant increase in gastric mucosal blood flow (GMBF) as measured to the entire stomach or a large segment of the stomach. The increase in GMBF is interpreted as a compensatory response of the stomach to acid or chemical injury. However, when GMBF to the site of erosion formation is measured, focal mucosal ischemia has been demonstrated. To further define the role of GMBF in acute gastric mucosal ulcerogenesis, the proposed studies are designed to 1) determine the mediator or the vasodilator responsible for this overall increase in GMBFk, 2) characterize the microcirculatory changes that result in focal ischemia and, 3) examine factors that may protect against focal ischemia. These studies will utilize an ex vivo mechanically-perfused segment of the dog's stomach. The first goal will be pursued by determining the time course of changes in gastric vascular resistance following mucosal exposure to ethanol and salicylates. These studies will use competitive antagonists and synthesis inhibitors to assess the role of endogenous histamine, adenosine, and prostaglandins as mediators of the overall increase in GMBF during injury. The second aim will be achieved by identifying microvascular events associated with the development of focal mucosal ischemia. In this regard these experiments will determine the relative significance of effects of leukotrienes, proulcerogenic actions of platelet activating factor, involvement of granulocytes in capillary obstruction, and changes in vascular permeability resulting in edema development. The last objective will be accomplished by assessing the protective effect of factors which reduce the severity of focal mucosal ischemia. Several vasodilators such as adenosine analogues, prostaglandins, and isoproterenol will be tested for the degree of protection against focal ischemia and salicylate or ethanol-induced ulcers. These proposed studies will provide new insight into the patho-physiology of acute gastric ulcers. Clinical application of such knowledge may be beneficial in the prevention and treatment of superficial erosive diseases of the gastric mucosa.